Dataset Information

Comprehensive Structure-Activity Profiling of Micheliolide and its Targeted Proteome in Leukemia Cells via Probe-Guided Late-Stage C—H Functionalization

ABSTRACT: The plant-derived sesquiterpene lactone micheliolide was recently found to possess promising antileukemic activity, including the ability to target and kill leukemia stem cells. Efforts toward improving the biological activity of micheliolide and investigating its mechanism of action have been hindered by the paucity of preexisting functional groups amenable for late-stage derivatization of this molecule. Here, we report the implementation of a probe-based P450 fingerprinting strategy to rapidly evolve engineered P450 catalysts useful for the regio- and stereoselective hydroxylation of micheliolide at two previously inaccessible aliphatic positions in this complex natural product. Via P450-mediated chemoenzymatic synthesis, a broad panel of novel micheliolide analogs could thus be obtained to gain structure-activity insights into the effect of C2, C4, and C14 substitutions on the anti-leukemic activity of micheliolide, ultimately leading to the discovery of ‘micheliologs’ with improved potency against acute myelogenic leukemia cells. These late-stage C—H functionalization routes could be further leveraged to generate a panel of affinity probes for conducting a comprehensive analysis of the protein targeting profile of micheliolide in leukemia cells via pull-down experiments and proteomic analyses. These studies introduce new micheliolide-based anti-leukemic agents and shed light onto the biomolecular targets and mechanism of action of micheliolide in leukemia cells. More broadly, this work showcases the value of the present P450-mediated C—H functionalization strategy for streamlining late-stage diversification and elucidation of the biomolecular targets of a complex bioactive natural product.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Kevin Welle

LAB HEAD: Rudi Fasan

PROVIDER: PXD024455 | Pride | 2021-09-10

REPOSITORIES: Pride

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			Action	DRS
	Alwaseem_17-163.msf	Msf
	Alwaseem_Ctrl-14Black_17-163.raw	Raw
	Alwaseem_Ctrl-14Blue_17-163.raw	Raw
	Alwaseem_Ctrl-2Black_17-163.raw	Raw
	Alwaseem_Ctrl-2Blue_17-163.raw	Raw

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Comprehensive Structure-Activity Profiling of Micheliolide and its Targeted Proteome in Leukemia Cells via Probe-Guided Late-Stage C-H Functionalization.

Alwaseem Hanan H Giovani Simone S Crotti Michele M Welle Kevin K Jordan Craig T CT Ghaemmaghami Sina S Fasan Rudi R

ACS central science 20210428 5

The plant-derived sesquiterpene lactone micheliolide was recently found to possess promising antileukemic activity, including the ability to target and kill leukemia stem cells. Efforts toward improving the biological activity of micheliolide and investigating its mechanism of action have been hindered by the paucity of preexisting functional groups amenable for late-stage derivatization of this molecule. Here, we report the implementation of a probe-based P450 fingerprinting strategy to rapidly ...[more]

PMID: 34079900

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